1. Field of the Invention
This invention relates generally to ion sensors, and more particularly relates to chloride ion-selective-electrode sensors and for methods for production of sensors having improved selectivity and stability in repeated use.
2. Description of the Related Art
Solid state ion-selective-electrode (ISE) sensors that measure the activity or concentration of analyte ions and metabolites are useful in the analysis of biological sample fluids including blood, urine, plasma, saliva, spinal fluid, and serum. Such sensors often use a polymeric membrane incorporating an ion-selective agent or ion-sensing element with the ability to complex or otherwise attach to the desired analyte and produce an electrical response. The magnitude of the electrical response to the analyte is defined as the sensitivity. In use, sample fluids are brought into direct contact with the membrane layer requiring that the membrane's sensitivity remain constant during repeated exposure to fluids, elsewise the sensor will produce inaccurate or spurious measurements and have a limited uselife. Sensors that measure chloride ions often use tridodecylmethylammonium chloride (TDMAC) as an ionophore. Unfortunately, the fluids in contact with the sensor can extract the TDMAC out of the membrane causing the sensitivity uselife of thin ISE sensors to be limited. This is particularly problematic when heparinized plasma samples are analyzed, because the heparin has been found to adversely affect TDMAC, possibly by extraction of TDMAC or contamination of the sensor surface or other mechanisms, and has been determined to limit the sensor life to about 200 uses. Uselife is generally defined as the exposure of the sensor to fluids that is required to cause a change in the calibration slope by more than 10%. Herein, uselife is defined by the number of hours a sensor is in contact with a standard test fluid comprising a standard aqueous solution of sodium and potassium chloride and carbonate having a pH in the range about 9.0 to 9.5 and an ionic strength of approximately 150 millimolar or as the number of plasma samples required to cause this change.
Another requirement of the sensor is having a minimal response to species in samples other than the analyte of interest, a characteristic known as selectivity. Body fluids, urine and blood in particular, often contain substances such as drugs and various ionic species which can also complex or attach to the membrane and so produce a spurious electrical response. In the design of sensors that determine the chloride content in blood and urine, a particularly difficult challenge is achieving a high selectivity over ions like salicylates (in blood and urine) and/or other similar ions. and maintaining this selectivity during repeated exposure to blood and urine samples.
There is general theoretical understanding of the requirements for producing sensitivity within an ISE sensor membrane, however, theory has poor predictive value for defining the chemical structure of a membrane required to obtain good initial sensitivity and selectivity and to retain these characteristics during actual use.
It is known to improve the selectivity of an ISE sensor by employing a plasticizer having an alkyl or phenyl group to which a "functional group" bonds (U.S. Pat. No. 5,112,471). This approach uses a high dielectric constant plasticizer in order to maintain a favorable ionic dissociation.
It is also known to improve the selectivity and accuracy of anion-selective membranes by using tetra-alkyl, quaternary phosphonium salts having four relatively large alkyl radicals. Such salts have a relatively low positive charge density and greater steric hindrance, which results in weaker interactions with ions which sometimes improves selectivity for large hydrophobic ions (U.S. Pat. No. 5,116,481).
Other efforts to improve the durability of sensors used a semi-permeable membrane to protect an underlying electrolyte layer from species such as metal ions, which may prove harmful to their intended operation, while passing species such as water vapor and oxygen necessary for their operation (U.S. Pat. No. 5,401,376). Such membranes are provided with a degree of flexibility to allow the underlying electrolyte layer to swell and contract while adhering to that layer.
It is evident from the foregoing that a remaining shortcoming in chloride ISE sensors is degradation in the sensor membrane's sensitivity and selectivity as a result of repeated exposure to sample fluids containing the analyte of interest as well as substances other than the analyte of interest. In addition, extending the uselife of a chloride sensor by increasing the stability of its selectivity without adversely affecting the sensor's sensitivity is of commercial interest and also presents significant design challenges.